Identification of Genes Involved in Major Mood Disorders

National Institute Of Mental Health

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Abstract

NCT00001174 We conducted the first genome-wide association study (GWAS) of bipolar disorder (BD) in 2007. The results implicated several genes of small effect, suggesting that BD is a polygenic disease. Last year, the Psychiatric Genomics Consortium (PGC) Bipolar Disorder Workgroup, in which we are active collaborators, completed an additional GWAS with over 50,000 cases, the largest to date. The results identified 64 genome-wide significant loci, over half of which are novel. Together common risk variants account for almost one-third of the inherited risk of bipolar disorder. Implicated genes are enriched for targets of antipsychotics, calcium channel blockers, antiepileptics, and other novel drugs. An additional collaborative study published in 2021 showed that suicide attempts which all too often occur in people living with BD -- are associated with additional genetic risk factors shared by people with depression, smoking, risk-taking, and insomnia. The results suggest a shared underlying biology between suicide attempts, known suicide risk factors, and psychiatric disorders. Additional collaborative studies were published in recent years. The results show that response to lithium therapy in BD is significantly associated with genetic variation in immune-modulating genes, genes previously associated with risk for schizophrenia, depression, or ADHD, as well as key clinical variables. This body of work aims to develop genetic tests that might identify patients most likely to benefit from lithium therapy. In a separate study, we collaborated with Seth Ament and colleagues on a GWAS of BD and related disorders in the Old Order Amish (OOA), a population with a unique genetic history. The analysis revealed 4 genome-wide significant risk loci, all of which were associated with over 2-fold increased risk, and 2 of which were apparently novel. The lead SNPs at all four loci were uncommon outside of the OOA, and lead SNPs at 3 of these loci were also associated with lifetime depressive symptoms. Network analysis suggested that the risk loci harbor novel risk-associated genes that interact with known neuropsychiatric risk genes. This study demonstrated the power of special populations to detect relatively high-risk alleles in BD and related disorders. Large GWAS also provide a valuable set of reference data for calculating polygenic risk scores (PRS) that capture the combined influence of many genes of small effect. We are exploring ways in which the PRS can be used to better understand individual differences in the onset, course, and presentation of BD. For example, we recently published a study of PRS to address the high rates of comorbid anxiety in BD, a largely unexplained phenomenon. Results showed that among individuals with BD, genetic risk for anxiety is associated with comorbid anxiety disorders and unexpectedly with recurrent suicide attempts. In other samples, anxiety showed more genetic overlap with depression and neuroticism than with BD itself. These findings suggest that comorbid anxiety in BD reflects partly non-overlapping contributions of bipolar and anxiety-related genes. Treatments that address this dual genetic burden may improve outcomes in BD with comorbid anxiety. To identify rarer genetic variants that may have a larger impact on risk for major mood disorders, we have undertaken genome sequencing studies in families and special populations. So far, we have collected more than 1200 individuals from Amish and Mennonite (Anabaptist) communities whose unique genetic history makes them especially good candidates for this kind of study. All blood samples are processed by the Rutgers Cell and DNA Repository which distributes DNA as a resource for the general scientific community. In addition to psychiatric diagnostic assessments, participants are asked to complete tests of cognition and dimensional measures of mood and anxiety. These data will allow us to better characterize the range of phenotypes present in carriers of risk genes, many of whom are not expected to have diagnosable mental illness. Skin or blood cells donated by selected participants are reprogrammed into induced pluripotent stem cells for functional genomic studies (see ZIA-MH002810). We have now created the largest psychiatrically phenotyped collection of Anabaptists, with over 1687 participants in over 511 families ascertained in the US, Brazil, and Canada. This longitudinal sample comprises clinical diagnoses, dimensional phenotypes, cognitive assessments, DNA, SNP arrays, exome sequence, and induced pluripotent stem cells (iPSC) that will serve as a research resource for years to come. This living catalog of neuropsychiatric phenotypes and genetic variants comprises known and novel CNVs, damaging rare variants in neurodevelopmentally important genes, and a cohort of study participants who are readily available for follow-up phenotyping, genetic testing, treatment studies, or other future priorities. We have found several large copy number variants (CNVs) that have been previously implicated in psychiatric disorders. In collaboration with Morgan Similuk and colleagues at NIAID, we are reaching out to participants diagnosed with a psychiatric illness who carry CNVs with a well-established role in psychiatric illness and offer these participants the opportunity to hear about their genetic findings and undergo formal genetic counseling. We are measuring mood, anxiety, perceived stigma, and understanding of the genetic information we present. We hope this study will provide our study participants with useful information about contributing factors in their own illness, while generating valuable data concerning the impact of genetic diagnosis on psychiatric patients who carry high-risk genetic changes. During the COVID-19 pandemic, we reached out to recent study participants to investigate the impact of the pandemic and associated life stressors on their mental health. Surveys of stress, anxiety, mood, and general well-being, and a modified version of the CoRonavIruS Health Impact Survey (CRISIS) were sent to hundreds of past participants at approximately 6-month intervals. Data from the first set of respondents showed that those with high levels of anxiety or psychological distress before the pandemic were also more likely to report increased depressive symptoms during the pandemic. This was especially true for those who reported more lifestyle changes during the pandemic. These results suggest that baseline mental health predicts depressive symptoms during the pandemic, esp. among those with more exposure and distress. Such individuals may benefit from targeted support and services. This year we also performed a pilot study of the potential role of de novo mutations (DNMs) as a contributing factor to BD. DNMs are genetic changes that arise anew as DNA is passed from parents to offspring and have already been shown to play an important role in mental illnesses such as autism and schizophrenia. Exomes of about 1200 individuals in almost 200 families were examined. DNMs with expected harmful impacts on gene function were found in 42 separate genes. Genes with DNMs were enriched for functions related to learning, post-synaptic organization, nervous system development, and calcium ion transport. These genes also overlapped with brain co-expression modules associated with neurogenesis and immunity. These findings support a role for DNM in BD and highlight roles for neurodevelopment and immunity. Genes with significant burdens of DNMs would be excellent candidates for functional genomic studies. Next year we will enroll additional participants, perform more exome sequencing, expand genetic association analyses in larger samples, provide genetic counseling to additional participants, and finish the COVID-19 impact study.